Conventional imaging diagnosis, for example X-ray computer tomography (CT), magnetic resonance tomography (MRT), positron emission tomography (PET), single photon emission computed tomography (SPECT) or optical imaging such as NIRF (Near Infra Red Fluorescence) provides anatomical or functional physiological information about the body. In this case, contrast agents are often used to make pathological tissue visible via physiological parameters such as blood supply or tissue density.
In PET, for example, biomolecules in which a stable isotope is replaced by a positron emitter, for example 11C, 13N or 15O, are used as contrast agents (CA). In this way, it is possible to monitor the metabolic behavior of the labeled biomolecules. Paramagnetic or ferromagnetic substances, for example chelated Gd or iron oxide nanoparticles, are used in MRT as contrast agents which can accumulate on further molecules for functionalization. These contrast agents concentrate, for example, in tissues which may be pathologically modified, where they lead to contrast changes in the image.
Currently approved contrast agents, however, are not very specific. Concentration of the MRT contrast agent Gd-DOTA in the brain may, for example, be caused by a tumor, a stroke, an MS lesion or any other physiological modification which affects the blood-brain barrier.
More recent so-called molecular imaging (MI) contrast agents allow very much more specific characterization of pathological tissues by the aforementioned imaging methods (see A. Hengerer, T. Mertelmeier, Siemens AG, Medical Solutions, Erlangen, Germany: “Molecular Biology for Medical Imaging” electromedica 69 (2001) no. 1).
Molecular imaging integrates molecular biological methods, for example antigen-antibody interactions or peptide receptor binding, and imaging technologies. In this way, noninvasive characterization of biological processes is possible at the cellular or molecular level. Molecular imaging thus involves the in vivo visualization of defective metabolic processes by biological reagents (molecular imaging contrast agents) which bind to molecular disease markers or target structures in the body and hence label them selectively. As a supplement to conventional imaging, molecular imaging provides complementary information about the position and—in the ideal case—the amount of molecular target structures in the living body, without the need for a biopsy.
Since pathological processes first manifest themselves at the molecular level, before (macro-) anatomical or functional expressions of the disease occur, molecular imaging allows diagnosis in the early stages of a disease.
A molecular imaging contrast agent therefore includes both a contrasting unit, for example an iron oxide nanoparticle in the case of MRI, and a molecular structure which interacts with the target structure in the tissue.
This molecular structure is also referred to as the “ligand” of the contrast agent.
WO 99/56788 discloses a method for the selection of a suitable molecular imaging contrast agent for a particular target tissue. This may be a cell culture or a tissue sample. In the method, a large number of different contrast agents are generated by the conjugation of contrasting units with a multiplicity of different ligands, for example peptides, oligomers, synthetic monomers or antibodies etc. The contrast agents are added to the target tissue and the binding affinity is tested by an analytical method.
The article by K. P. C. Li et al., “Combined vascular targeted imaging and therapy: a paradigm for personalized treatment”, Journal of Cellular Biochemistry, ISSN 1097-4644, 2002, Supplement 39, 65-71, discloses a nanoparticle technology for loading particles both with ligands that bind to target structures and with contrasting units and therapeutic active agents. The nanoparticles respond, in particular, to endothelial receptors. Before treatment with a nanoparticle for administering a pharmaceutical active agent, the affinity of this nanoparticle can be tested by “in vivo” imaging after having administered a nanoparticle which is loaded with a contrasting unit but not with the therapeutic active agent.
In many applications, MI contrast agents are so specific that imaging examination cannot be carried out with the same contrast agent on every patient, even if they have the “same” initial diagnosis/suspected diagnosis. Many diseases that are currently grouped under one diagnosis (for example tumors of particular organs) actually subsume various molecular diseases with anatomically similar expression. Since the underlying pathological mechanisms are different, however, there may also be different target structures for the imaging.
In order to exploit the possibilities of specific molecular imaging contrast agents, each patient must thus undergo the same imaging method several times, with a different contrast agent in each case. If a contrast agent is selected with only one particular ligand that binds to particular molecular disease marks, then no diagnosis if is possible if the contrast agent has been selected incorrectly.